Recent findings on Hodgkin's disease (HD) present a number of important questions. The established risk factors point to age of infection as an important modifier of risk. Cases have altered antibody profiles to the Epstein-Barr virus (EBV) preceding and following diagnosis. The new finding is that 30-50% of HD cases' tumors contain monoclonal EBV genome, with a restricted latent protein expression. How these risk factor, serologic, and molecular data fit together and whether EBV-genome negative HD represents a separate etiology are unknown. This Program Project is designed to test three alternate models of the role of the EBV in the pathogenesis of HD: the EBV is solely related to EBV-genome positive HD with EBV-genome negative disease due to non-viral causes; HD is a virally induced malignancy with the EBV responsible for EBV-genome positive disease and another unidentified virus(es) linked to EBV- genome negative disease; or the EBV plays a crucial early role in the pathogenesis of essentially all HD cases but the genome is selectively lost in some patients. Three companion projects will address the following: the role of EBV in the epidemiology of HD (600 cases and 600 population controls); the association of pre- diagnosis EBV serology with EBV genome status of tumor biopsy in HD (200 cases and 200 matched controls); and characterization of the EBV infection and the cellular immune response in HD cases (160 cases and 160 bone marrow donor controls). The Projects are supported by a serology/pathology Core and an Administrative Core. The combined mutually standardized data from the population studies, plus extensive biomarkers including EBV serology and viral probes, and detailed immunologic markers will result in a substantial and rich database. The program brings together an experienced multi- disciplinary group of investigators; by working together we should gain insight into the etiology of HD.